Synthesis and biological activity of novel symmetrical bis-2- phenyliminothiazolidine derivatives

Article abstract of DOI:10.1080/10426500600865103

A series of novel symmetrical bis-2-phenyliminothiazolidine derivatives were designed and synthesized. The structures of all the title compounds were characterized by ¹H NMR and, in some cases, by ¹³C NMR, IR, and high-resolution mas

Full text of DOI:10.1080/10426500600865103

Phosphorus, Sulfur, and Silicon, 181:2851–2861, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600865103
Synthesis and Biological Activity of Novel Symmetrical
Bis-2-phenyliminothiazolidine Derivatives
Gang-Yue Li
Electromechanics and Materials Engineering College, Dalian Maritime
University, Dalian, Liaoning Province, People’s Republic of China; and
State Key Laboratory of Fine Chemicals, Dalian University of
Technology, Dalian, Liaoning Province, People’s Republic of China
Xu-Hong Qian
Institute of Pesticides and Pharmaceuticals, East China University of
Science and Technology, Shanghai, People’s Republic of China; and
State Key Laboratory of Fine Chemicals, Dalian University of
Technology, Dalian, Liaoning Province, People’s Republic of China
Sheng-Gang Yan
Electromechanics and Materials Engineering College, Dalian Maritime
University, Dalian, Liaoning Province, People’s Republic of China
Jing-Nan Cui
State Key Laboratory of Fine Chemicals, Dalian University of
Technology, Dalian, Liaoning Province, People’s Republic of China
Qing-Chun Huang
Institute of Pesticides and Pharmaceuticals, East China University of
Science and Technology, Shanghai, People’s Republic of China
Rong Zhang
Feng-Yu Liu
Da-Wei Cui
State Key Laboratory of Fine Chemicals, Dalian University of
Technology, Dalian, Liaoning Province, People’s Republic of China
Received February 26, 2006; accepted May 4, 2006.
This project was supported by the National Key Project for Basic Research
(2003CB114400) and the National Natural Science Foundation of China.
Address correspondence to Xu-Hong Qian, State Key Laboratory of Fine Chemicals,
Dalian University of Technology, P.O. Box 89, Zhongshan Road 158, Liaoning Province,
Dalian 116012, People’s Republic of China. E-mail: xhqian@ecust.edu.cn
2851

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G.-Y. Li et al.
A series of novel symmetrical bis-2-phenyliminothiazolidine derivatives were
designed and synthesized. The structures of all the title compounds were char-
1
13
acterized by H NMR and, in some cases, by C NMR, IR, and high-resolution
mass spectra. Herbicidal activities were examined, and some of these compounds
showed selectively herbicidal activity against Triticum aestivum. The type of
linker between the two 2-phenyliminothiazolidines was crucial for the biological
activities.
Keywords Bis-2-phenyliminothiazolidine; herbicidal activity; selectivity; synthesis
INTRODUCTION
With the occurrence of herbicide-resistant weeds,1 it is necessary to
develop efficient herbicides with novel structures or modes of action.
Heterocycle compounds play a very important role in drug design and
synthesis, owing to their unique bioactivities. Nitrogen- and sulfur-
containing heterocycle compounds, 2-iminothiazolidine derivatives,
have gained much interest as potent inhibitors of indoleethylamine N-
methyltransferase,2−3 octopaminergic-agonists,4−5 anthelmintics,6−7
diuretic agents,8 trehalase inhibitors,9−11 and insecticidal agents.12
However, few 2-iminothiazolidine derivatives with herbicidal activity
were reported, and these mainly involved 2-acyliminothiazolidines,
2-sulfonyliminothiazolidines, and 2-phenyliminothiazolidines.13 It was
presumed that this class of compounds probably possesses herbicidal
activities.
Linking two pharmacophores to obtain high bioactivity or selectiv-
ity is a common method in the design of new pharmaceuticals and
agrochemicals.14−18 Herein, we designed and synthesized a series of
novel symmetrical bis-2-phenyliminothiazolidine derivatives by adopt-
ing 2,6-dimethylenepyridine and a di-thiourea group containing a ben-
zene ring as the linker between two 2-phenyliminothiazolidines. The
results of the bioassay showed that some of these compounds exhibited
selective herbicidal activity against Triticum aestivum.
RESULTS AND DISCUSSION
Synthesis
2-Phenyliminothiazolidines intermediates X were prepared, as shown
in Scheme 1, according to the reported procedure.19 The reaction of
ethanolamine with aryl isothiocyanates gave thioureas, which were
directly used in the next step. The cyclization of thioureas and con-
centrated HCl and then the neutralization with aqueous 10 M NaOH
gave the required 2-phenyliminothiazolidines X in the range of 85–99%

Novel Symmetrical Bis-2-phenyliminothiazolidine Derivatives
2853
SCHEME 1 The synthetic scheme for compounds A.
yields, which were also used directly in the next step without further
purification.
Target compounds A were prepared by the reaction of 2,6-
dichloromethylpyridine with the anion of 2-phenyliminothiazolidines,
which were generated by a treatment of 2-phenyliminothiazolidines
with sodium hydride in dry acetonitrile (Scheme 1).
Syntheses of target compounds B needed the key intermediate
m-xylylenediisothiocyanate Y, which was commonly prepared by the
reaction of carbon disulfide and dicyclohexylcarbodiimine in Et2O, but
with a low yield. Therefore, we adopted a different method as shown
in Scheme 2. The reaction of m-xylylenediamine with carbon disulfide
in the presence of triethylamine gave the corresponding triethylam-
monium dithiocarbamate salt. After slowly adding ethyl chloroformate
with an ice-bath cooling, m-xylylenediisothiocyanate Y was obtained in
an 81% yield.
The target compounds B were prepared as shown in Scheme 2.
The reaction of m-xylylenediisothiocyanate Y with the corresponding
2-phenyliminothiazolidines X using DBU as a catalyst gave compounds
B in a 66–99% yield. The structures of all the target compounds were
well characterized by 1H NMR and, in some cases, by 13C NMR, IR, and
high-resolution mass spectra (HRMS) (Tables I and II).
Biological Activity
Herbicidal activities against Setaria viridis, Eclipta prostrasta, Cu-
cumis sativus, Chenopodum serotinum, T. aestivum and Amaranthus
SCHEME 2 The synthetic scheme for compounds B.

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G.-Y. Li et al.
TABLE I Experimental Data of Target Compounds
HRMS[M + H+]
Calculated Found
Molecular
Formula
Compound
R
Yield (%)a
M.P. (◦C)
A1
A2
A3
A4
A5
A6
A7
A8
B1
B2
B3
B4
B5
B6
B7
B8
H
2-CH3
2-Cl
4-Cl
2-F
37
33
33
35
34
30
34
29
84
87
99
71
97
99
89
66
96.5–97.9 C25H25N5S2
109.5–110.5 C27H29N5S2
460.1630 460.1640
488.1943 488.1939
161.0–162.2 C25H23Cl2N5S2 528.0850 528.0864
145.5–146.9 25H23Cl2N5S2 528.0850 528.0841
133.5–135.0 C25H23F2N5S2
133.9–135.3 25H23F2N5S2
C
496.1441 496.1452
496.1441 496.1454
532.1253 532.1245
596.1377 596.1371
577.1337 577.1341
605.1650 605.1642
4-F
C
2,4-F, F
2-CF3
H
2-CH3
2-Cl
4-Cl
2-F
4-F
2,4-F, F
2-CF3
109.2–110.5 C25H21F4N5S2
114.3–115.5 C27H24F6N5S2
147.9–149.0
C28H28N6S4
116.5–118.0 C30H32N6S4
129.0–130.4 C28H26Cl2N6S4 645.0557 645.0545
138.0–139.4 28H26Cl2N6S4 645.0557 645.0563
164.7–166.7 C28H26F2N6S4
168.7–170.3 28H26F2N6S4
C
613.1148 613.1130
613.1148 613.1130
649.0926 649.0942
713.1084 713.1065
C
167.4–168.9 C28H24F4N6S4
146.3–147.8 C30H27F6N6S4
aYield determined by isolation based on X.
mangostanus were measured according to the method described in the
experimental section. Among all the compounds, A3, A4, A5, and A6
possessed selective herbicidal activities against T. aestivum instead of
S. viridis, E. prostrasta, C. sativus, C. serotinum, and A. mangostanus.
The herbicidal activity of A5 against T. aestivum reached 86% at
500 mg L−1
.
From these results, it was found that the type of linker between the
two 2-phenyliminothiazolidines was crucial for biological activities. In
study on pharmaceuticals and agrochemicals, the introduction of pyri-
dine into a parent compound may improve biological activities of the
compounds.20−22 Most compounds A with the pyridine linker exhib-
ited selective herbicidal activity against T. aestivum, but compounds B
exhibited a loss of bioactivity owing to an increase in the length and
rigidity of the linker.
In addition, we studied on the relationship between the type of sub-
stituent R on a phenyl ring and biological activities. Compounds with a
halogen-substituted phenyl ring showed good biological activities (A3,
A4, A5, and A6), but the compounds with a poly-fluorine–substituted
phenyl ring showed a loss of biological activities (A7). This is probably
because the fluorine atom is a lipophilic group, and the introduction of
poly-fluorine excessively decreases the hydrophilicity of the molecule
and furthers the bioactivities. Further research on the modification of
the structure is proceeding.

Novel Symmetrical Bis-2-phenyliminothiazolidine Derivatives
2855
TABLE II IR and 1H NMR Data of Target Compounds
Compound IR νmax(KBr,cm−1
)
1H NMR or 13C NMR δ (ppm, CDCl3/TMS)
A1
1641, 1589, 1239,
1143, 764, 696
3.18 (t, J= 7.0 Hz, 4H), 3.70 (t, J= 7.0 Hz, 4H), 4.86
(s, 4H), 6.95 (d, J= 8.0 Hz, 4H), 7.04 (t, J= 7.6 Hz,
2H) 7.26–7.34 (m, 6H), 7.68 (t, J= 7.6 Hz, 1H)
2.12 (s, 6H), 3.17 (t, J= 6.8 Hz, 4H), 3.75 (t, J= 6.8
Hz, 4H), 4.87 (s, 4H), 6.85 (d, J= 7.6 Hz, 2H),
6.96 (t, J= 7.6 Hz, 2H), 7.08–7.16 (m, 4H), 7.33
(d, J= 7.6 Hz, 2H), 7.68 (t, J= 7.6 Hz, 1H)
3.21 (t, J= 6.8 Hz, 4H), 3.82 (t, J= 6.8 Hz, 4H), 4.96
(s, 4H), 6.94–7.04 (m, 4H), 7.18 (t, J= 7.2 Hz, 2H),
7.36 (d, J= 7.6 Hz, 2H), 7.53 (d, J= 7.2 Hz, 2H),
7.75 (t, J= 7.2 Hz, 1H)
A2
1632, 1592, 1232,
1143, 763
A3
A4
1637, 1578, 1232,
1142, 761
1608, 1581, 1231,
1131, 831
13C NMR (125 MHz, CDCl3, ppm) δ 27.10, 51.19,
51.74, 121.14, 123.07, 123.93, 127.19, 127.45,
129.65, 137.56, 149.12, 156.51, 159.69 3.18 (t,
J= 6.8 Hz, 4H), 3.71 (t, J= 6.8 Hz, 4H), 4.83 (s,
4H), 6.87 (d, J= 8.4 Hz, 4H), 7.22 (d, J= 8.4 Hz,
4H), 7.28 (d, J= 7.6 Hz, 2H), 7.68 (t, J= 7.6 Hz,
1H)
A5
A6
A7
A8
1633, 1603, 1244,
1145, 753
3.20 (t, J= 7.0 Hz, 4H), 3.77 (t, J= 7.0 Hz, 4H), 4.89
(s, 4H), 6.90–7.10 (m, 8H), 7.37 (d, J= 7.6 Hz, 2H),
7.70 (t, J= 7.6 Hz, 1H)
1619, 1574, 1232,
1150, 838
3.17 (t, J= 7.0 Hz, 4H), 3.71 (t, J= 7.0 Hz, 4H), 4.83
(s, 4H), 6.84–6.91 (m, 4H), 6.96 (t, J= 8.4 Hz, 4H),
7.29 (d, J= 7.6 Hz, 2H), 7.68 (t, J= 7.6 Hz, 1H)
3.21 (t, J= 7.0 Hz, 4H), 3.77 (t, J= 7.0 Hz, 4H), 4.86
(s, 4H), 6.73–6.85 (m, 4H), 6.86–6.95 (m, 2H), 7.34
(d, J= 7.6 Hz, 2H), 7.70 (t, J= 7.6 Hz, 1H)
3.20 (t, J= 6.8 Hz, 4H), 3.76 (t, J= 6.8 Hz, 4H),
4.85 (s, 4H), 7.02 (d, J= 8.0 Hz, 2H), 7.08 (d,
J = 7.6 Hz, 2H), 7.34 (d, J= 7.6 Hz, 2H), 7.42 (t,
J= 7.6 Hz, 2H), 7.57 (d, J= 7.6 Hz, 2H), 7.71 (t,
J= 7.6 Hz, 1H)
1624, 1591, 1242,
1138, 846, 816
1640, 1598,1234,
1121, 758
B1
B2
1604, 1584, 1243,
1171, 762, 693
13C NMR (125 MHz, CDCl3, ppm) δ 27.09, 50.98,
51.70, 120.98, 122.40, 122.74, 122.80(d, J= 28.75
Hz), 124.23(d, J= 271.25 Hz), 126.28(d, J= 5.0
Hz), 132.35, 137.57, 150.52, 156.49, 158.90
3.12 (t, J= 7.0 Hz, 4H), 4.84 (t, J= 7.0 Hz, 4H),
4.89 (d, J= 4.4 Hz, 4H), 6.89 (d, J= 7.6 Hz, 4H),
7.14 (t, J= 7.6 Hz, 2H), 7.22–7.38 (m, 8H), 12.59
(s, 2H, –NH)
1610, 1594, 1238,
1174, 761
13C NMR (125 MHz, CDCl3, ppm) δ 25.08, 49.65,
54.96, 121.28, 125.08, 126.56, 126.71, 129.03,
129.22, 137.58, 148.44, 158.64, 180.17 1.98 (s,
6H), 3.12 (t, J= 7.0 Hz, 4H), 4.83–4.90 (m, 8H),
6.82 (d, J= 8.0 Hz, 2H), 7.04 (t, J= 6.8 Hz, 2H),
7.10–7.17 (m, 4H), 7.22–7.26 (m, 3H), 7.31 (s, 1H),
12.59 (s, 2H, –NH)
(Continued on next page)

2856
G.-Y. Li et al.
TABLE II IR and 1H NMR Data of Target Compounds (continued)
Compound IR νmax(KBr,cm−1
)
1H NMR or 13C NMR δ (ppm, CDCl3/TMS)
B3
1614, 1586, 1235,
1176, 749
3.14 (t, J= 7.0 Hz, 4H), 4.82–4.98 (m, 8H), 6.96 (d,
J= 7.6 Hz, 2H), 7.04 (t, J= 7.6 Hz, J= 8.0 Hz,
2H), 7.19 (d, J= 7.6 Hz, 2H), 7.23–7.28 (m, 3H),
7.32–7.37 (m, 3H), 12.40 (s, 2H, –NH)
B4
B5
B6
B7
B8
1614, 1592, 1244,
1174, 820
3.14 (t, J= 7.0 Hz, 4H), 4.80–4.90 (m, 8H), 6.81 (d,
J= 8.8 Hz, 4H), 7.20–7.33 (m, 8H), 12.42 (s, 2H,
–NH)
3.16 (t, J= 7.0 Hz, 4H), 4.84–4.92 (m, 8H), 6.92–
6.98 (m, 2H), 7.03–7.11 (m, 6H), 7.24–7.28 (m,
3H), 7.34 (s, 1H), 12.47 (s, 2H, –NH)
3.13 (t, J= 7.0 Hz, 4H), 4.78–4.94 (m, 8H), 6.80–
6.88 (m, 4H), 6.96–7.04 (m, 4H), 7.21–7.31 (m,
3H), 7.33 (s, 1H), 12.50 (s, 2H, –NH)
3.17 (t, J= 7.0 Hz, 4H), 4.84–4.92 (m, 8H), 6.78–
6.95 (m, 4H), 7.22–7.30 (m, 5H), 7.32 (s, 1H), 12.40
(s, 2H, –NH)
1615, 1555, 1236,
1181, 760
1603, 1589, 1246,
1180, 837
1618, 1553, 1240,
1177, 845, 810
1613, 1596, 1247,
1158, 767
3.15 (t, J= 7.0 Hz, 4H), 4.80–4.94 (m, 8H), 7.00 (d,
J= 8.0 Hz, 2H), 7.17–7.24 (m, 5H), 7.28 (s, 1H),
7.48 (t, J= 8.0 Hz, 2H), 7.59 (d, J= 8.0 Hz, 2H),
12.14 (s, 2H, –NH)
From the results shown in Table IV, it was found that compounds A
and B exhibited different electronic properties, hydrophobicity, and
spatial properties owing to the linker’s variation and substituents on
the phenyl ring. Compounds A presented a smaller molecular vol-
ume, a bigger dipole moment, higher energy of the lowest unoccu-
pied molecular orbital, higher net charges on the N1 atom, and lower
net charges on the N2 atom than compounds B, and these might be
the reasons that compounds A were active but compounds B were
inactive. In addition, the values of lg P, EL, QN1, and QN2 of com-
pounds with bioactivity remained in the range from 2.32 to 3.07,
TABLE III Herbicidal Activities of Compoundsa at 500 mg L−1
Average Growth Inhibitory Rate (%)
Compound
R
Triticum aestivum
A3
A4
A5
A6
2-Cl
4-Cl
2-F
53
73
86
48
4-F
aThe results of effective compounds were listed.

2857

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G.-Y. Li et al.
from −0.5652 to −0.4894, from −0.0433 to −0.0479, and from −0.1243
to −0.1209, respectively. This indicated that for compounds possess-
ing bioactivity, it was necessary that their electronic parameters and
hydrophobicity lie in a suitable range.
CONCLUSIONS
In conclusion, we have demonstrated that the novel symmetrical bis-2-
phenyliminothiazolidine derivatives with a pyridine linker presented
selective herbicidal activity against T. aestivum. It was found that the
activity of such compounds against T. aestivu could be strongly related
to the electronic properties and hydrophobicity. Future structural mod-
ification and biological evaluation should be carried out to explore the
full potential of this novel class of herbicidal molecules.
EXPERIMENTAL
Melting points were obtained with an X-6 micro-melting point appara-
tus and are uncorrected. IR spectra were recorded on a Nicolet 20DXB
FT-IR spectrometer using potassium bromide pellets or films. 1H NMR
spectra were measured on a Varian INOVA-400 spectrometer with
chemical shifts reported as an parts per million (in CDCl3, TMS as
an internal standard). 13C NMR spectra were measured on a Bruker
AVANCE-500 spectrometer (in CDCl3, TMS as internal standard). Mass
spectra were measured on an HP 1100 LC-MSD HRMS were obtained
on an HPLC-Q-Tof MS (micro) spectrometer. Flash chromatography
was performed on silica gel. All of the solvents were analytical grade.
All chemicals or reagents were purchased from standard commercial
suppliers.
General Synthetic Procedure for 2-Phenyliminothiazolidines X
To a solution of ethanolamine (0.305 g, 5.0 mmol) in 50 mL of chloroform
was added dropwise the corresponding aryl isothiocyanate (5.0 mmol)
over a period of 10 min, and the mixture was stirred at r.t. for about
2 h. Then the solvent was evaporated under vacuum, and the residue
was washed with diethyl ether and water to afford thiourea, which
was used directly in the next step without further purification. The
corresponding thiourea (5.0 mmol) was dissolved in hydrochloric acid
(10 mL) and heated at 90◦C for 45 min. The mixture cooled in an ice
bath was basified with 10 M NaOH. The precipitated residue was fil-
tered and washed with water to give a white solid X in an 85–99%
yield.

Novel Symmetrical Bis-2-phenyliminothiazolidine Derivatives
2859
The Synthesis of M-xylylenediisothiocyanate Y
m-Xylylenediamine (6.8 g, 50 mmol) was dissolved in anhydrous diethyl
ether or the minimum amount of benzene and reacted with carbon disul-
fide (9.12 g, 120 mmol) and triethylamine (10.1 g, 100 mmol) at r.t. After
complete precipitation of the triethylammonium dithiocarbamate salt,
the mixture was filtered. The solid was washed with anhydrous diethyl
ether and air dried for about 10 min. Then the solid was dissolved in
chloroform (50 mL), treated with triethylamine (10.1 g, 100 mmol), and
cooled to 0◦C. To this solution was added ethyl chloroformate (10.8 g,
100 mmol) dropwise over a 15-min period with violent stirring. The
mixture was allowed to warm to r.t. and was stirred for about 1 h. The
solvent was distilled off under reduced pressure, and the residue was
purified by column chromatography on silica gel by using petroleum
ether/dichloromethane (5/1, v/v) as an eluent to give Y in an 81% yield.
General Synthetic Procedure for the Target Compounds A
2-Phenyliminothiazolidine (10 mmol) was added to a suspension of
sodium hydride (0.6 g, 25 mmol) in dry acetonitrile (15 mL) and
DMF (0.5 mL). After stirring for 0.5 h at r.t. a solution of 2,6-
dichloromethylpyridine (5 mmol) in dry acetonitrile (10 mL) and a little
KI as a catalyst were added. The reaction was refluxed for 3–8 h. The
solvent was distilled off under reduced pressure, and the residue was
purified by silica column with 20% acetone/petroleum ether as an eluent
to give white solid A in a 29–37% yield.
General Synthetic Procedure for the Target Compounds B
A mixture of m-xylylene diisothiocyanate Y (0.22 g, 1.0 mmol) and
2-phenyliminothiazolidines X (2.0 mmol) in benzene (25 mL) was re-
fluxed for about 1 h with a drop of DBU (1,8-diaza-bicyclo [5.4.0]undec-
7-ene) as a catalyst. The excess of benzene was then distilled off under
reduced pressure, and the residue was purified by column chromatog-
raphy on silica gel by using dichloromethane as an eluent to give the
white solid B in a 66–99% yield.
Biological Assay and Molecular Parameters
The herbicidal activities of the target compounds were measured with
the method described as follows. Each sample was dissolved in DMF,
and then the solution was diluted with emulsifier 0201 (a mixture of
anionic and nonionic surfactant) containing water (0.1 g L−1) until the

2860
G.-Y. Li et al.
FIGURE 1 The demonstration of the net charge (e.g., compound A-1).
required concentration was achieved. The biological tests were carried
out in plastic boxes. Nineteen mL of 0.9% thawed water agar and 1 mL
of diluted solution were added to the plastic boxes and shaken. After
the drug-containing agar was cool, the seeds of S. viridis, E. prostrasta,
C. sativus, C. serotinum, T. aestivum, and A. mangostanus were sowed,
and then the cultivations were kept at 24 1◦C with exposure to light
of 3000 LX for 7 days. The growth inhibitory rates (%) of the target
compounds related to the control were determined. The results of com-
pounds demonstrating activity are listed in Table III.
The molecular total energy (ET), the energy of the highest occupied
molecular orbital (EHOMO), energy of the lowest unoccupied molecular
orbital (ELUMO), net charges on the N and S atom (QN and QS) (Figure 1),
dipole moment, volume V, and the molecular hydrophobicity parame-
ter (lg P) were calculated with Hyperchem Software (2002 edition) of
Hypercube, Inc. Before all parameters of a compound were calculated,
its spatial molecular conformation was also optimized with Hyperchem
to acquire its lowest energy conformation. All descriptor data are listed
in Table IV.
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